Natural killer T cells accelerate atherogenesis in mice

• Published in: Blood 2004-10, Vol.104 (7), p.2051-2059
• Main Authors: Nakai, Yukihito, Iwabuchi, Kazuya, Fujii, Satoshi, Ishimori, Naoki, Dashtsoodol, Nyambayar, Watano, Keiko, Mishima, Tetsuya, Iwabuchi, Chikako, Tanaka, Shinya, Bezbradica, Jelena S., Nakayama, Toshinori, Taniguchi, Masaru, Miyake, Sachiko, Yamamura, Takashi, Kitabatake, Akira, Joyce, Sebastian, Van Kaer, Luc, Onoeé, Kazunori
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD1 - biosynthesis; Antigens, CD1d; Apolipoproteins E - metabolism; Arteriosclerosis - etiology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Bone Marrow Cells - cytology; Bone Marrow Transplantation; Cardiology. Vascular system; Diet, Atherogenic; Flow Cytometry; Glycolipids - metabolism; Interferon-gamma - metabolism; Killer Cells, Natural - pathology; Leukocytes, Mononuclear - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Spleen - cytology; T-Lymphocytes - pathology; Th1 Cells - immunology; Time Factors; Transgenes
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-10-3485

We have investigated the potential role of CD1d-restricted natural killer T (NKT) cells in the development of atherosclerosis in mice. When fed an atherogenic diet (AD), NKT cell-deficient CD1d-/- mice had significantly smaller atherosclerotic lesions than AD-fed C57BL/6 (wild-type [WT]) mice. A significant reduction in atherosclerotic lesions was also demonstrated in AD-fed, low-density lipoprotein receptor-deficient (Ldlr-/-) mice reconstituted with CD1d-/- bone marrow cells compared with the lesions observed in Ldlr-/-mice reconstituted with WT marrow cells. In addition, repeated injections of α-GalCer or the related glycolipid OCH to apolipoprotein E knockout (apoE-/-) mice during the early phase of atherosclerosis significantly enlarged the lesion areas compared with mice injected with vehicle control. However, administering α-GalCer to apoE-/- mice with established lesions did not significantly increase the lesion area but considerably decreased the collagen content. Atherosclerosis development in either AD-fed WT or apoE-/- mice was associated with the presence of Vα14Jα18 transcripts in the atherosclerotic arterial walls, indicating that NKT cells were recruited to these lesions. Thioglycolate-elicited macrophages pulsed with oxidized low-density lipoproteins expressed enhanced CD1d levels and induced NKT cells to produce interferon-γ, a potentially proatherogenic T-helper 1 (TH1) cytokine. Collectively, we conclude that NKT cells are proatherogenic in mice. (Blood. 2004;104:2051-2059)